Our objective is to characterize the effects of ligand-induced ErbB4 signaling on the behavior of human breast, prostate, and pancreatic tumor cell lines. We have four specific aims: (1) Establish tumor cell model systems and determine the effects of ligand-induced ErbB4 signaling. (2) Determine the mechanisms by which ErbB4 is coupled to downstream biological effects. (3) Assess the role of ErbB receptor heterodimerization in coupling ErbB4 ligands to downstream biological effects. (4) Determine the structure of the ErbB4 extracellular domain bound to various NRG isoforms and mutants. A hypothesis that will be emphasized throughout this effort is that different Neuregulin isoforms differentially stimulate ErbB4 signaling and coupling to biological responses. The results of these experiments will shed new insight into the pathogenesis of breast, prostate, and pancreatic cancers. Moreover, they will suggest potential strategies for the treatment of these diseases.